Basic research on prefrontal cortex (PFC) functioning has established a specific cognitive and behavioral profile of patients afflicted by lesions in this region, that is characterized by a decline in performance in tasks that require focused attention, inhibition, or action sequencing in goal achievement. Research in clinical psychology has revealed a similarly suboptimal cognitive style in the majority of patients diagnosed with depression, as indicated by pronounced difficulties in decision-making, perseverations on, particularly negative, interpretations of life events, and ineffectiveness in task completion. Recent developments in clinical neuroscience have suggested that neurodevelopmental abnormalities in prefrontal regions are critically associated with major depression. Specifically, different types of abnormalities in the dorsolateral prefrontal (DLPFC) and orbitofrontal (OBC) cortices, anterior cingulate cortex (ACC), and basal ganglia are hypothesized to underlie the brain circuit pathophysiology linked to the disorder. Despite recent research on the identification of such PFC anomalies, few studies have investigated individual differences among patients on how abnormalities in these areas affect performance on a variety of cognitive tasks and how they are associated with treatment effectiveness and therapeutic outcomes. The primary aim of the present project is to establish a strong partnership between the clinical and neuroscience communities of the University of Pennsylvania that will focus on the development of translational research between basic behavioral/neuroscience research on PFC function and clinical research on depression. We aim to initiate a research program that will explore the relationships between the deficient cognitive profile in depression (i.e., disruptions in normal cognitive and motor inhibition, attentional disturbances, and impulsivity) and a certain physiological profile as characterized by PFC-limbic system abnormalities. The focus of this project is to develop a set of new methodologies that will provide more detailed neurocognitive assessments of hypofrontal functioning in depression that will allow for better characterization of different patient subgroups. The present research program incorporates diverse and novel methodologies including behavioral, perfusion fMRI, transcranial magnetic stimulation (TMS), and neuropsychological/clinical studies, and introduces a novel set of tasks that will allow for a better characterization of hypofrontal cognitive profile in normal subjects, as well as its manifestation in different populations of depressed patients. Through the development of a comprehensive set of neurocognitive assessment procedures we will be able to better characterize different populations of patients diagnosed with depression based on lateral PFC hypo- functioning and to make specific predictions on the effectiveness and outcome of different treatment plans. Finally, we aim to collect exploratory data in support of the development of a larger-scale, long-term research plan promoting interdisciplinary research on the diagnosis and treatment of depression based on the relationship between PFC functioning and specific cognitive and mood profiles of different patient subgroups that can be used to guide optimal clinical practice. Research on the frontal lobes has established a specific cognitive and behavioral profile of patients afflicted by lesions in this region, which is characterized by a decline in performance in tasks that require focused attention and memory. Research in clinical psychology has revealed similar problems in patients diagnosed with depression, as indicated by their difficulties in decision-making and their negative interpretations of life events. Different types of abnormalities in regions of the prefrontal cortex are hypothesized to underlie the behavioral and cognitive problems linked to this disorder. Despite recent research on the brain pathology of depression, few studies have investigated individual differences among patients on how this pathology affects performance on a variety of cognitive tasks and how it is associated with treatment effectiveness and therapeutic outcomes. The goal of this project is to improve our understanding of basic behavioral processes and brain involvement in cognitive tasks in depression, which will lead to more accurate diagnoses and to the selection of the most suitable treatment approaches for individual patients. RELEVANCE: Research on the frontal lobes has established a specific cognitive and behavioral profile of patients afflicted by lesions in this region, which is characterized by a decline in performance in tasks that require focused attention and memory. Research in clinical psychology has revealed similar problems in patients diagnosed with depression, as indicated by their difficulties in decision-making and their negative interpretations of life events. Different types of abnormalities in regions of the prefrontal cortex are hypothesized to underlie the behavioral and cognitive problems linked to this disorder. Despite recent research on the brain pathology of depression, few studies have investigated individual differences among patients on how this pathology affects performance on a variety of cognitive tasks and how it is associated with treatment effectiveness and therapeutic outcomes. The goal of this project is to improve our understanding of basic behavioral processes and brain involvement in cognitive tasks in depression, which will lead to more accurate diagnoses and to the selection of the most suitable treatment approaches for individual patients.